Chronic hepatitis B is a significant public health problem, affecting approximately 400 million people globally. It remains the 10th leading cause of mortality worldwide despite the availability of an effective vaccine. Many viral and host factor have been implicated in disease progression and hepatocarcinogenesis, but most of the studies were based on retrospective analyses with limited longitudinal data. Currently, seven agents are FDA-approved for the treatment of chronic hepatitis B. Each of these agents was reported to have virological, biochemical and histological benefits for both HBeAg positive and negative disease. However, none of these agents, used as monotherapy, can effectively eradicate HBV. The Harvard Hepatitis B Consortium was selected as one of the Clinical Centers of the NIDDK-sponsored Hepatitis B Research Network (HBRN) in North America. We have been working collaboratively with the other 11 clinical centers, the Data Coordinating Center (DCC), and the Immunology Center within the HBRN in the past 6 years. Over 1800 ethnically diverse patients are being monitored and characterized in the Cohort study. In addition, there are two clinical trials designed to evaluate the efficacy of combination therapy with pegylated interferon and an antiviral agent for the immune tolerant and immune active adult patients. Both trials are actively enrolling patients. To date, the Harvard Hepatitis B Consortium contributed between 8% and 8.5% of the patients in the Cohort study and the Immune Active clinical trial respectively. Naturally occurring HBV variants such as basal core promoter (BCP) and precore (PC) mutations are usually the dominant viral species in HBeAg negative disease. In a recent study based on the HBRN cohort, BCP and PC variants were identified as the dominant species in a surprisingly high prevalence of HBeAg positive patients. In this ancillary study, we propose to utilize the available clinical data and biospecimen repository from the enrolled patients to understand the roles of these HBV variants in the natural history and treatment responses of chronic hepatitis B. Collectively, the long term observation database, the rich biospecimen repository, the ancillary studies and the clinical trial results generated by the HBRN will undoubtedly yield valuable insights into the natural history, immunopathology, pathogenesis and optimal therapy for this important disease.